 And I'd like to also thank the KCA organizer, organizers, the leadership of Bill Pro and Gary Konoski for putting this together. These are my disclosures. So as you saw in Dr. Wood's talk, the treatment landscape for Iansakasinoma has witnessed a revolution in a very short period of time. In seven years, we saw the approval by the FDA of seven agents after a drought of 13 years since the approval of Hydrozyl-2. Within a month, Surafinib and Sunitinib came to the market in December 2005 for Surafinib, and in January 2006, Sunitinib was FDA-approved. In 2007, the first mTOR inhibitor, Temsiralamus, was approved. And in 2009, we saw the approval of three agents or three therapies, Everolimus, Bivacizumia plus interferon-alpha, and Pozopinib. And in January 2012, Acitinib was FDA-approved. This slide summarizes for you the target therapies that are licensed in the US for treatment of metastatic renal cell cancer. I'd like to draw your attention that two of these, Everolimus and Acitinib, are approved for the second line or salvage therapy. And the other five are approved, as you see in the first, in the right-hand column, for the treatment of metastatic renal cell casinoma, irrespective of line. You see here the targets of these different therapies, the route of administration. Five of these are oral to our intravenous. And you see also the target of these agents. Now, four of these are what we refer to tyrosine kinase inhibitors. These are the drugs that are taken by mouth. And they target the tyrosine kinase inhibitor, specifically VGF receptor. And two belong to the class of mTOR inhibitors. This is a summary of the first line, phase three trials conducted for the metastatic renal cell casinoma. The top two combine B. vasusimab, which is a monoclonal antibody against VEGF and interferon alpha. Then bazapinib, synitinib, tyrosinib, and acitinib are tyrosine kinase inhibitors, as I mentioned. And thamsinolimus is an mTOR inhibitor. You see the control arm in the fourth column, and then the number of patients enrolled on these trials, on each of these arms, and the primary endpoint. I think I would like to discuss the bottom two trials first, because these are drugs that were not approved for the indication they were conducted in. And that's tyrosinib and acitinib. Tyrosinib and acitinib are referred to as novel or second generation tyrosine kinase inhibitors, because they are more potent against the primary target, VEGF receptors. And they are more selective. They do not have the off-targets, the other kinases that the synitinib, soraphinib, and bazapinib, the older generation or first generation, have. These two trials, tyrosinib and acitinib, were compared to soraphinib in the first line, and you see the number of patients. And they had for primary endpoint, progression-free survival. They did not meet the primary endpoint, because the acitinib had a 78% aim of improving progression-free survival compared to soraphinib. That was an ambitious goal. And the idea was to do the trial faster and to do it in a smaller number of patients. And unfortunately, while acitinib had a longer progression-free survival than soraphinib, it did not meet the endpoint of 78% improvement. So it was not FD approved for the first line treatment of patients with metastatic clearsaria sarcosinoma. Tyrosinib versus soraphinib. While the primary endpoint was MET, which was progression-free survival and was improved with the second generation tyrosinib versus soraphinib. However, the problem with the trial is that patients who were treated with soraphinib in the first line had the opportunity to cross over after progressing on soraphinib and receive tyrosinib. While patients who received tyrosinib in the first line, very few of them crossed over to receive a second line therapy. So it ended up being, when you look at survival, it ended up being comparing a group of patients receiving one line of therapy, and that's tyrosinib, versus a group of patients that received two lines of therapy, therapies soraphinib followed by tyrosinib. So the survival of the group of patients who received soraphinib was better than the survival of patients who received tyrosinib in the first line. So that's why the FDA did not approve tyrosinib. And we'll move on and discuss briefly the other trials starting with synitinib. This was a phase three trial comparing patients with interferon alpha, the old standard, given at the standard dose and scheduled 9 million three times per week, versus synitinib, 50 milligram daily on the standard schedule of four weeks or two weeks off. It was a large phase three trial of 750 patients. The primary endpoint was progression free survival. And patients who were recruited to the trial, if they had, you see the box there of eligibility criteria, predominantly clear cell and no prior systemic therapy, measurable disease, good performance status and adequate organ function. The secondary endpoints were overall survival, objective response rate, patient reported outcomes and safety. And you see the couple in my curves showing that patients treated with synitinib represented here in blue had a better progression free survival, a median of 11 months versus five months median progression free survival for patients treated with interferon alpha. This was a statistically significant difference between the two arms. Then we have two trials combining B. vasusimab plus interferon. These were very similar in design, represented in this schema here. One was conducted in the US by the CA-LGB cooperative group and included 732 patients. And one was conducted mostly in Europe by Avoren, the Avoren trial. It had 649 patients. The difference between these two studies is that patients on the Avoren trial were required to have prior nephrectomy before enrolling on the trial. And the treatment also comprised placebo in addition to B. vasusimab, placebo for B. vasusimab. Whereas the CA-LGB did not mandate prior nephrectomy and there was no placebo control. Primary endpoint of the trial was OS, secondary endpoints, PFS, objective response rate, and safety. And as you see here in the two Kaplan-Meier curves for the Avoren study as well as the CA-LGB trial study, patients treated with the combination of B. vasusimab plus interferon had a better progression free survival, represented in the green curve compared to patients who were treated with just interferon alpha or interferon alpha plus placebo. However, patients did not have a superior survival. The survival of patients on these two arms was not significant. And the reason was patients after coming off these two trials had the opportunity to receive other target therapies and that confided the survival. Same thing we saw with the previous trial I showed you with synetonym versus interferon. While there was a trend for improvement of overall survival in the patient's treat with synetonym compared to interferon alpha, this was did not cross the threshold of becoming significant, again, because patients received other target agents after coming off Pral. And then there was 25 patients who were crossed over from interferon to synetonym. The other phase three trial was the global ARCC trial. This was a phase three trial of TEMSIRALMS, the mTOR inhibitor, versus interferon alpha versus the combination of TEMSIRALMS plus interferon alpha. The primary endpoint of this trial was overall survival. Patients were recruited who had any histological type of RCC. 80% of those patients had the common type, cleav cell or conventional histology, and 20% had the other non-cleave, what we refer to as non-cleav cell histology. But importantly, for patients to be eligible for the trial, they had to have three or more risk factors to enroll in the trial. And here you see the Kaplan-Meier curves, again showing a separation of the curves patients treated with TEMSIRALMS had a superior survival compared to patients who were treated with interferon, represented in blue, or the combination represented in pink. The median survival for patients treated with TEMSIRALMS was 10.9 months versus 7.3 months median overall survival for patients treated with interferon alpha, an improvement of 49%. So that led to the approval of this agent for RCC. The next study was the Pazopenib phase III study. This was a study conducted, sponsored by Glasgow Smith Klein. It was conducted mostly in Europe. Patients had to have cliocell histology, but there were two cohorts of patients, one cohort previously treated with cytokines and one cohort treatment naive. There was two-to-one randomization in that two patients were randomized to receive Pazopenib versus placebo. The primary endpoint was progression-free survival. And here are the curves for patients treated with Pazopenib represented in the yellow curve. The median progression-free survival was 11 months. Again, similar to what you saw in the study with synitinib versus interferon alpha. Patients treated with placebo had a median survival of about three months. Again, significant difference, and this led to the approval of Pazopenib. Again, as I mentioned with the other trials, 48% of patients treated with placebo when they had progressive disease with placebo were given the opportunity to cross over and receive Pazopenib after progression. And this led to, again, the confounding impact on survival. When you look at median survival for these two cohorts, there was no statistically significant difference in overall survival, again, because of the cross over and subsequent therapies patients received after the study. So, of what I mentioned, it looked like the two front runners for the treatment of metastatic RCC in the first line were synitinib where you had the best results and Pazopenib where you had also the best results. So these were the two front runners. Although Bivacizumab plus interferon had, you would think, comparable efficacy, it did not catch on in terms of applicability in the clinic because patients had to receive, would have to receive an infusion every two weeks plus injection of interferon three times per week. So, it was no surprise that GSK decided to have this trial that we can compare trial, comparing the two front runners, Pazopenib versus synitinib, for first line treatment of metastatic RCC. This was a large phase neutral of 1110 patients conducted in multiple continents. It had the design of non-inferiority for progression-free survival. In other words, they wanted to show if Pazopenib is non-inferior to synitinib when it comes to efficacy, looking at the progression-free survival as primary endpoint. And there were secondary endpoints, overall survival, objective response rate, duration of response, safety and quality of life. And here are the results. Pazopenib was found to be not inferior to synitinib and if looking at the progression-free survival, which was the primary endpoint. And when you look at the secondary survival, which is important, secondary endpoint, the median survival for patients treated with Pazopenib and synitinib was similar, about two and a half years. However, very importantly, there were differences in toxicity and quality of life. In 16 out of 16 quality of life domains, Pazopenib was felt to be better tolerated by improved quality of life tools compared to synitinib. And toxicity favored Pazopenib because patients had less fatigue and less hand-foot skin reaction, less mind-of-suppression. The next study that GSK sponsored, and this was recently published in the Journal of Clinical Oncology, this was a patient preference. It was a double-blind design comparing Pazopenib versus synitinib in a double-blind fashion. So the patient didn't know what they were taking and the physicians treated did not know what they were taking. And ultimately, patients were told at the end of the study, which directed they prefer, was it the first one, which was given for 10 weeks, then two weeks break, then they switched, or the other way around. So this was 160 patient trials, so it was a phase two trial, and the results were in favor of Pazopenib by a margin of 70% to 20%. Also in blue, this was tracked by the physicians, 61 versus 22% of patients, physicians also preferred or voted for Pazopenib as the preferred agent. But the story doesn't end here because quality of life tools were administered in the previous trial compares at a time at the end of the cycle for synitinib 29 days, every 29 days. And that for patients who have received synitinib will tell you that this is the peak when they have the most adverse events. So now after eight years of synitinib, we have alternative schedule to give this drug instead of the standard four weeks on two weeks off. Retrospective study from our institution as well as other institutions have shown that patients who received synitinib with the two weeks on one week off schedule have less adverse events. And there is a suggestion that patients will have a better survival because they can stay on treatment longer. So the jury is still out which would be the preferred agent upfront? I think there's no question that both drugs are good drugs. Now what about second line and beyond? I will go quickly through those phase three trials. This was the first trial with the target agents, the target trial compared Saurafenib versus placebo in patients who had cytokine and prior therapy. The primary endpoint was OS, secondary endpoint was progression free survival. And here are the coupling mild curves. In blue are patients treated with Saurafenib. In red are patients treated with placebo. There was a statistically significant difference in progression free survival. Patients with a treat with Saurafenib had immediate progression free survival of 5.5 months compared to 2.8 months. But the overall survival because again, as happens with the other trials, there was a crossover at progression. There was no statistically significant difference between the two arms. The record one phase three trial compared Ivarulimus after Saurafenib versus placebo. This was a two to one randomization. Again, twice the number of phases were randomized to receive Ivarulimus plus best supportive care versus placebo plus best supportive care. The primary endpoint was progression free survival. And again, the results were in favor of Ivarulimus over placebo. Again, these are patients who were treated previously with a tyrosine kinase inhibitor, either Saurafenib or synatinib. The other study phase three trial was the access study and it randomized patients to receive either exitinib or Saurafenib after receiving either synatinib first line or bivacizumab plus interferon or temseralamus or cytokine. And then the results are here. Patients treated with exitinib represented in yellow curve had an improved progression free survival with a median of 6.7 months compared to Saurafenib with a median of 4.7 months. However, it's important to note that the best results were in patients who received exitinib after receiving prior immunotherapy. So the median progression free survival with exitinib after immunotherapy was 12 months. If you look at given exitinib after synatinib, the median progression free survival was 4.8 months. But all of these were in favor of exitinib. There is an important study that compared temseralamus and Saurafenib. So this is the first time we're comparing an mTOR inhibitor versus Saurafenib in the second line after synatinib. So all these patients here were treated with synatinib first and had progressive disease. And then now they're assigned to receiving either the mTOR inhibitor, temseralamus or Saurafenib. The primary endpoint was progression free survival. And then when you see the curves, although numerically, temseralamus had a better progression free survival median 4.28 versus 3.9. This was not statistically significant. But what was statistically significant and of concern was the survival was surprising and anticipated in that patients who were treated with Saurafenib after synatinib, so TKI after TKI had a four month difference improved survival compared to patients who received temseralamus. So suggesting that maybe given a TKI followed by TKI tyrosine kinase inhibitor against VGF would be a better strategy than giving a TKI followed by an mTOR inhibitor. The last phase three trial I would like to show is this gold trial, it's a phase three trial of the vitinib versus Saurafenib in patients with clear cellular soccasinoma who had a tyrosine kinase inhibitor for first line, an mTOR inhibitor, evronimus for the second line. And then they are randomized to receive either this BFGF receptor inhibitor because BFGF was implicated to be a pathway responsible for resistance to angiogenesis inhibitor versus Saurafenib. The results were negative in that the progression free survival was not statistically significantly different between the two arms, patients receiving third line the vitinib, the BFGF receptor inhibitor had a median BFS of 3.7 months compared to 3.6 months with Saurafenib. Survival median was 11 months for both arms and the response rate with each agent was very low 4%. So what about combinations and sequential therapies? In one word, there is no combination of two target agents that is more helpful or more efficient, more effective than a single agent except for the combination of BFGF plus interferon alpha that I discussed. So the question is if patients do not achieve a complete response, does it matter what you start with? And here are trials that are addressing that question. This is a trial conducted in Germany was presented two months ago at the ASCO GU comparing two sequences of two tyrosine kinase inhibitors Saurafenib followed by synitinib versus synitinib followed by Saurafenib. The results were not surprising while the patients who received synitinib first had a two months improvement of their progression free survival compared to Saurafenib. When you look at time on therapy from first line to second line, there was no significantly difference between the two arms. The record three is a phase two trial comparing a mTOR inhibitor, everolimus versus synitinib. This was presented at ASCO last year. It has not been published yet. The results show superiority of synitinib over everolimus in the first line. And there is also concern here similar what we saw with the intersect when we give them Sauralimus in the second line after a tyrosine kinase inhibitor. The patients who received everolimus first followed by synitinib. There was a trend for inferior survival compared to patients who received synitinib followed by everolimus. Now toxicity is an unpleasant and unwelcome thing patients have to go through when they're receiving these therapies. But this is a double a sword. Patients have, if they have developed the hypertension or hypothyroidism, hand foot skin reaction, fatigue with these tyrosine kinase inhibitors. We looked at these and we find that patients who have these actually do better than patients who do not develop these toxicities. So while toxicities maybe are definitely untoward and unpleasant and unwelcome, they suggest that patients who develop these toxicities have a better outcome or respond better to these therapies. We and others showed that in response to mTOR inhibitors developing pneumonitis is associated with also improved survival in patients treated with the mTOR inhibitors. These patients who develop hypercholesterolemia while receiving everolimus or termoterolemus also are predicted to do better. What about non-clear cell? These are, this is the list of the 2004 WHO classification of the renal tumors, you know, papillary, chromophob, translocation, renal medullary, collecting duct, musinistubular spindle cell and others. What do we do for these patients? As I showed you, the majority of the trials in RCC have been conducted in clear cell. What about the non-clear cell? In a word, there is no established therapy for the non-clear cell. That's why it's important to do these clinical trials. And these, this is a list of some of these ongoing phase two trials in non-clear cell RCC. I'd like to briefly show you some of these trials we're doing here at MD Anderson. This is the ESPN trial or everolimus versus synitinine prospective evaluation in non-clear cell RCC. We just completed accrual on this trial and it's been selected for oral presentation at ASCO. Patients with non-clear cell RCC with metastatic disease are randomized to receiving everolimus, the empty inhibitor, versus synitinine and at disease progression that cross over, results will be presented at ASCO. So maybe next year I'll share with you those results. We are still conducting the star trial and this is a sequential two-agent assessment in the Riyansak Cosynomotherapy in patients with clear cell who have already had their nephrectomy. We're looking at six sequences. We chose three drugs, one representing each class, Bivacuzumab representing the antibody against the EGF, Pazopin and the tyrosine kinase inhibitor and everolimus, the mTOR inhibitor. The goal and the goals of these trials is to come to precision medicine, try to identify patients who respond to one of these agents and try to understand why patients who respond to one of these agents lose their response and have progressive disease. So this is a very tissue-rich trial with a lot of correlative studies that will be crucial and informative once we complete the trial. We're at 170 patients for a total of 240 patients. The TEMPA trial is an ongoing trial for clear cell RCC patients who have poor risk disease and it's comparing Pazopinib versus the standard of care for patients with poor risk, the tyrosine kinase. We have 30 patients enrolled on the trial toward a goal of 90 patients. So conclusion, we have seven target agents that have been approved. Improvement in progression-free survival has been shown with all agents and improvement in OS with one agent tyrosine kinase but complete responses are rare. Early and active management of adverse events will minimize those delays, those reductions or treatment discontinuations and may impact long-term benefit. Adverse events may be predictive biomarkers of therapeutic benefit. Sequential therapy is the standard of care in 2014 but the optimal sequence tyrosine kinase inhibitor followed by tyrosine kinase inhibitor or tyrosine kinase inhibitor followed by mTOR inhibitor remains to be determined. There is no established systemic therapy for advanced Montglisal RCC, unfortunately, but the hope is that insights into the biology of rheosoccusenoma will be essential and will help us to identify relevant targets and improved therapies. There is still a role, as you will hear later from my colleague, Dr. Gao, for all the immunotherapy will hide those IL-2 and there is a promising wave of agents on the horizon with the immune checkpoint blockade, Nevalumab and Epidumumab and they represent the next strategy for achieving a breakthrough in the treatment of metastatic rheosoccusenoma trials combining novel immune therapies with each other and target therapies are ongoing. In the era of target therapy, is there a cure for a patient with metastatic rheosoccusenoma? I would like to finish on a positive note because I'd like to leave you with a message of hope. This is a patient that I saw from Pensacola, Florida eight years ago, presented with hematuria, weight loss, left varicoseal and workup showed a mass in his left kidney. We were going to enroll him on one of the trials Dr. Wood showed you, pre-surgical trial with B. vasusima. Unfortunately, we found he had metastasis in the brain so he was not eligible. So we went on and treated him with Thoraphanem because that was the first agent that came out and he received it for 16 weeks, had transient response and had progressive disease and developed in addition to the brain metastasis and lung metastasis, which I'll show you, he developed metastasis in bone and liver. So we start them with Sunitinib and you can see here, after several months of treatment with Sunitinib, his metastatic disease in the lungs resolved, metastatic disease in the brain resolved, the primary tumor as you see shrink significantly and the metastatic disease in the lymph nodes improved, as you can see, in the liver resolved, in the bone healed, you could see the hole in his thoracic, in his lumbar vertebra, how the newborn formation, brain, without treating him for the brain with radiation, whole brain radiation or surgery or gamma knife, the tumor is in the brain resolved and look at the tumor and then after five and a half years of Sunitinib, we decided we should take that kidney out, although initially it would have been unwise to do surgery up front in somebody who has metastatic disease to brain, lungs, bone and liver. So we proceeded when he developed hypertension after five years of therapy, we stopped Sunitinib and after we controlled his blood pressure, went on and took his kidney out and there was no viable tumor in his left kidney. I saw him two months ago, two years after stopping Sunitinib, he has no evidence of recurrence. Next month will be two years since he had his nephrectomy, he's eight years without recurrence. I would like to end this because this is why we're here today to give you hope and I wanna thank you personally, you the patients and your families for your trust and for participating in our clinical trials. You are the heroes who inspire us and remind us of the urgency of our research to make cancer history. Thank you.